This invention relates generally to the field of pyridine chemistry, and, more particularly to an improved process for preparing 2-methyl-3,5-dialkylpyridine derivatives.
Pyridine, with its characteristic aromatic ring structure, is the parent to a large number of substituted homologues and derivatives having uses in valuable industrial, pharmaceutical and agricultural chemicals. One such derivative is 2,3,5-trimethylpyridine, which is also known by the name 2,3,5-collidine.
For example, the compound 2,3,5-trimethylpyridine has recently proven valuable as a key intermediate for the synthesis of a highly-substituted pyridine derivative known as omeprazole, which has been accorded much medical and commercial interest because it and a family of related compounds have been found useful as gastric secretion inhibitors for treating ulcers and related diseases. U.S. Pat. No. 4,255,431, and U.S Pat. No. 4,337,257. However, while being an important raw material in the pharmaceutical world, 2,3,5-trimethylpyridine has been obtained previously only with much difficulty and expense.
For instance, one known process for preparing 2,3,5-trimethylpyridine is disclosed in U.S. Pat. No. 4,658,032, and comprises reacting 3,5-dimethylpyridine with a lower aliphatic alcohol (C.sub.1-4) in the presence of a Raney cobalt or nickel catalyst. However, the reaction described therein requires reaction pressures preferably in the range of 10 to 60 kg/cm.sup.2 and temperatures preferably in the range of 230.degree.-270.degree. C. Such pressures and temperatures are both difficult and expensive to achieve in industry. Additionally, the catalysts used are expensive and difficult to handle, particularly when commercial scale production is contemplated.
U.S. Pat. No. 4,658,032 in the background section also generally discusses three other known routes to 2,3,5-trimethylpyridine.
First, this compound may be obtained by separating and purifying 2,3,5-trimethylpyridine from shale oil contained in pitchstone or the like. However, this process is industrially disadvantageous because the amount of 2,3,5-trimethylpyridine present in the raw shale oil material is very small, and thus large quantities must be used to produce quantities of 2,3,5-trimethylpyridine sufficient to meet needs on an industrial level.
Second, 2,3,5-trimethylpyridine can be synthesized by bringing ammonia into contact with propionaldehyde and acetaldehyde in the presence of alumina at a reaction temperature of 340.degree. C. However, this process is unsatisfactory on an industrial scale because the yield of 2,3,5-trimethylpyridine is generally low.
Third, 2,3,5-trimethylpyridine may be produced by reacting 3,5-dimethylpyridine with methyllithium. This process, however, is disadvantageous in that methyllithium is very expensive and the use of this organic alkali metal compound, which is subject to decomposition by water or oxygen, is thought to be indispensable, and thus special care must be taken in handling this compound.
In light of the short comings of these previously known methods for preparing the compound 2,3,5-trimethylpyridine, there exists a need for an improved method for preparing the same which provides a good yield and does not require the use of disadvantageous temperatures or pressures, or of expensive materials or catalysts. The applicant's invention addresses this need.